Type of Document	Dissertation
Author	JING, ZHENG
Author's Email Address	zhj1@pitt.edu
URN	etd-08292008-125131
Title	The localization of c-Abl in Alzheimer's disease.
Degree	Doctor of Philosophy
Program	Neurobiology
School	School of Medicine
Advisory Committee	Advisor Name Title Robert Bowser Committee Chair Teresa G. Hastings Committee Chair Don DeFranco Committee Member J. Patrick Card Committee Member Ruth Perez Committee Member
Keywords	c-Abl Alzheimer's disease human hippocampus
Date of Defense	2008-07-14
Availability	restricted
Abstract The two major hallmarks of Alzheimer’s disease (AD) are amyloid plaques and neurofibrillary tangles (NFTs). Evidence suggests that the main component of amyloid plaques, β-amyloid peptide (Aβ) facilitates tau pathology via activation of specific kinases. Both glycogen synthase kinase-3β (GSK-3β) and cyclin-dependent kinase 5 (cdk5) have been demonstrated to be activated by Aβ and contribute to tau hyperphosphorylation. Recently, c-Abl has been implicated in Aβ-facilitated tau pathology by in vitro model systems. Alvarez et al. reported that c-Abl could be activated by Aβ in primary cultured neurons (Alvarez et al. 2004), and Derkinderen et al. found a novel phosphorylation site in paired helical filament tau (Tyr 394) that could be phosphorylated by c-Abl (Derkinderen et al. 2005). Moreover, Aβ has been shown to bind integrin receptors on the cell surface and transduce a signal from the extracellular space to the cell interior, regulating the cytoskeleton and/or gene transcription (Caltagarone, Jing et al. 2007). c-Abl can also be activated by integrin activation. Therefore, we hypothesize that c-Abl is associated with Aβ-facilitated tau phosphorylation via integrin binding and activation, contributing to the generation of AD pathology. We tested this hypothesis by examining the expression and distribution of c-Abl in the human hippocampus and by characterizing c-Abl interacting proteins in AD brain. We discovered that the activation state of c-Abl was altered during AD progression and c-Abl was associated with phospho-tau during AD. Preliminary co-immunoprecipitation data also suggested a possible association of c-Abl with another integrin signaling protein, paxillin. This study is the first to examine the expression and localization of c-Abl in healthy control and AD hippocampus, which contributes to our understanding of the functional role for c-Abl in AD pathogenesis. Interestingly, c-Abl was localized to granulovacuolar degeneration bodies (GVDs) during late-stage AD, a novel discovery that identifies a new protein component of GVDs in AD.
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